674698
research-article2016
TPP0010.1177/2045125316674698Therapeutic Advances in PsychopharmacologySD Filippis, I Cuomo
Therapeutic Advances in Psychopharmacology
Original Research
Does the efficacy of asenapine in bipolar disorder increase in the presence of comorbidity with a substance use disorder? A naturalistic study
Ther Adv Psychopharmacol 2017, Vol. 7(2) 67–77 DOI: 10.1177/ 2045125316674698 © The Author(s), 2016. Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions.nav
Sergio De Filippis, Ilaria Cuomo, Georgios D. Kotzalidis, Daniela Pucci, Pietro Zingaretti, Raffaella Porrari, Camilla Fini, Paola Motta, Matteo Caloro and Paolo Girardi
Abstract Background: Asenapine is a second-generation antipsychotic approved in Europe for treating moderate-to-severe manic episodes in adults affected by type I bipolar disorder (BD-I). We aimed to compare its efficacy in psychiatric inpatients with BD-I, with or without substance use disorder (SUD). Methods: We administered flexible asenapine doses ranging from 5–20 mg/day to 119 voluntarily hospitalized patients with Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR) BD-I diagnosis, with or without SUD. Patients were assessed with clinician-rated questionnaires [i.e. Brief Psychiatric Rating Scale (BPRS), Young Mania Rating Scale (YMRS), Hamilton Depression Rating Scale (HDRS), Hamilton Anxiety Rating Scale (HARS), and Global Assessment of Functioning (GAF)]. Assessments were carried out at baseline (T0, prior to treatment), and 3 (T1), 7 (T2), 15 (T3), and 30 days (T4) after starting treatment for all clinical scales and at T0 and T4 for the GAF. Results: Patients improved on all scales (p < 0.001) across all timepoints, as shown both by paired-sample comparisons and by applying a repeated-measures, generalized linear model (GLM). Patients without comorbid SUD showed greater reductions in BPRS scores at T2 and T3, greater reduction in YMRS scores at T3, and lower HARS scores at all timepoints. HDRS scores did not differ between the two groups at any timepoint. However, the reduction in HARS scores in the comorbid group was stronger than in the BD-I only group, albeit not significantly. Side effects were few and mild-to-moderate. Conclusions: The open-label design and the relatively short observation period may expose to both type I and type II statistical errors (false positive and false negatives). Asenapine showed effectiveness and safety in hospitalized BD-I patients. Its effect was stronger in patients without comorbid SUD.
Keywords: anxiety, asenapine, atypical antipsychotic drugs, bipolar disorder, substance use disorder
Introduction Bipolar disorder (BD) is a circular, chronic, progressive mood disorder characterized by major depressive episodes alternating with manic/hypomanic or mixed episodes [Judd et al. 2002; Leboyer and Kupfer, 2010]. BD with a history of a manic episode is type I (BD-I), whereas BD without manic episode history is type II [American Psychiatric Association, 1987, 2000]. Combined
estimated prevalence of type I and type II BD ranges from 0.5–2% [Warren and Dubovsky, 2013]. The prevalence of BD rises to 4.4–6.4% when adding subthreshold/subsyndromal forms [Merikangas et al. 2011]. BD is one of the main causes of disability worldwide, being associated to important psychological and social consequences, long-lasting
Correspondence to: Ilaria Cuomo, MD Villa von Siebenthal Neuropsychiatric Clinic, Genzano di Roma, Via della Madonnina 1, 00045 Genzano di Roma, Italy [email protected] Sergio De Filippis, MD Camilla Fini, MD Villa von Siebenthal, Genzano di Roma, Italy Department of Neurosciences, Mental Health, and Sensory Organs (NESMOS), School of Medicine and Psychology, Sapienza University, Rome, Italy Georgios D. Kotzalidis, MD, PhD Daniela Pucci, MD Matteo Caloro, MD Paolo Girardi, MD Department of Neurosciences, Mental Health, and Sensory Organs (NESMOS), School of Medicine and Psychology, Sapienza University, Rome, Italy Pietro Zingaretti, MSc Raffaella Porrari, MSc Paola Motta, MD Villa von Siebenthal, Genzano di Roma, Italy
http://tpp.sagepub.com 67
Therapeutic Advances in Psychopharmacology 7(2) unemployment, and medical comorbidity [Zimmerman et al. 2010; Merikangas et al. 2011]. BD has a high mortality rate that can be partly attributed to suicide (BD patients have the highest suicide risk after first hospital contact [Nordentoft et al. 2011] and their lifetime suicide attempt rate is 10–15%), to accidents, to a reckless dysmetabolizing lifestyle, and to the negative consequences of substance abuse [Craig et al. 2006; Khalsa et al. 2008; Young et al. 2013]. Due to its recurrent nature, patients present post-onset symptoms for almost half of their lives; this clinical and epidemiological finding imposes effective [Judd et al. 2002; Collins et al. 2011] and safe treatment that may ensure compliance, since the lack of treatment adherence is the most common cause of relapse or recurrence [Gutiérrez-Rojas et al. 2010]. Many second generation antipsychotics (SGAs) have been approved for acute, subacute, and maintenance treatment of BD. According to the World Federation of Societies of Biological Psychiatry (WFSBP) [Grunze et al. 2010] and to the Canadian Network for Mood and Anxiety Treatments (CANMAT) guidelines [Grunze et al. 2013], SGAs are first choice treatment in managing manic episodes, either in monotherapy or in association with mood stabilizers; quetiapine and olanzapine have obtained fair results also in the control of depressive episodes [Grunze et al. 2010, 2013; Yatham et al. 2013]. Asenapine has been recently approved in Europe for the treatment of moderate-to-severe manic episodes in adults, whereas in the US and some other countries it is used in the acute treatment of schizophrenia. Asenapine blocks 5-HT2A, 5-HT2B, 5-HT2C, 5-HT6 and 5-HT7 serotonin receptors, dopamine D2, D3 and D4 receptors, and α1A, α2A and α2C adrenoceptors [Szegedi et al. 2011; Azorin et al. 2013; Young et al. 2013]. Its moderate affinity for histamine receptors and almost complete lack of affinity for muscarinic acetylcholine receptors may explain its low propensity for metabolic changes [Potkin, 2011]. Clinical studies of asenapine to date showed efficacy in acute manic and mixed episodes [Panagides et al. 2007; McIntyre et al. 2010a], possibly in controlling depressive symptoms [Szegedi et al. 2011], and in maintenance [McIntyre et al. 2010b]. However, currently available data are insufficient for drawing conclusions, hence the need for further studies.
While there is consensus as to the importance of dopamine receptor blockade in mediating the antipsychotic effects of antipsychotics, and also regarding the importance of accumbens dopaminergic transmission in the maintenance of addictive behaviour [di Chiara et al. 2004], there is no clear indication for the use of atypical antipsychotics in the treatment of substance use disorders (SUDs). A study found clozapine to reduce symptoms of substance dependence more than olanzapine, and this has been attributed to the faster dissociation of the former from the D2 receptor [Machielsen and de Haan, 2009]. Although asenapine shows not so fast a dissociation from D2 receptors, it nevertheless blocks the D3 and D4 dopamine receptors, that have been linked to addiction [di Ciano et al. 2014; le Foll et al. 2014]. So it is possible that this drug improves sideways both the addiction and the psychosis. If true, we may expect a differential response of people with BD-I and SUD comorbidity. Our aim was to assess differences in the clinical response to asenapine between patients with BD-I patients alone and BD-I patients comorbid with SUD from a cohort of voluntarily hospitalized BD-I patients observed in a naturalistic setting. Material and methods Patients The study has been conducted in adult patients (aged 18–60) with BD- I who were voluntarily admitted between May 2014 and March 2015 at the Neuropsychiatric Hospital Villa von Siebenthal, Genzano, Rome, Italy. We recruited consecutive patients with DSM-IV-TR [American Psychiatric Association, 2000] BD-I on asenapine; each patient received the minimal effective dose. Diagnosis was confirmed through the Structured Clinical Interview for DSM-IV-TR Axis I Disorders (SCID-I) [First et al. 2002]. Patients who were on mood stabilizers or benzodiazepines were allowed to keep this regimen unaltered during the course of the study. Excluded were patients with neurological disorders, and intellectual disability. Assessment scales Patients were assessed through clinician-rated clinical scales and a functioning scale at baseline
68 http://tpp.sagepub.com
SD Filippis, I Cuomo et al. (T0, start of the treatment), 3 days later (T1), 1 week later (T2), 15 days later (T3), and 1 month later (T4, endpoint). To minimize errors, all evaluations for each patient were carried out by the same trained psychiatrist or psychologist (PM, CF, PZ, RP). Cohen’s κ for interrater reliability was 0.87 for all instruments used; p < 0.0001 (i.e. high). History and sociodemographic data were collected in a purposely constructed database, where annotation was made also for past drug treatment history and psychotropic drug use. The following clinical scales were completed at T0, T1, T2, T3, and T4: •• Hamilton Depression Rating Scale (HDRS) [Hamilton, 1960]: this is a scale sensitive to change that measures the severity of depressive symptoms. It contains an important proportion of somatic symptoms. It is a clinician-rated 21-item scale whose first 17 items are added to obtain the total score; single items are Likert, ranging 0–4 (8 items) or 0–2 (9 items); 0–7 is normal, 8–13 mild depression, 14–18 moderate depression, 19–22 severe depression and ⩾23 very severe depression. In antidepressant clinical trial research, a drop of at least 50% from baseline scores is considered as treatment response, while a score
research-article2016
TPP0010.1177/2045125316674698Therapeutic Advances in PsychopharmacologySD Filippis, I Cuomo
Therapeutic Advances in Psychopharmacology
Original Research
Does the efficacy of asenapine in bipolar disorder increase in the presence of comorbidity with a substance use disorder? A naturalistic study
Ther Adv Psychopharmacol 2017, Vol. 7(2) 67–77 DOI: 10.1177/ 2045125316674698 © The Author(s), 2016. Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions.nav
Sergio De Filippis, Ilaria Cuomo, Georgios D. Kotzalidis, Daniela Pucci, Pietro Zingaretti, Raffaella Porrari, Camilla Fini, Paola Motta, Matteo Caloro and Paolo Girardi
Abstract Background: Asenapine is a second-generation antipsychotic approved in Europe for treating moderate-to-severe manic episodes in adults affected by type I bipolar disorder (BD-I). We aimed to compare its efficacy in psychiatric inpatients with BD-I, with or without substance use disorder (SUD). Methods: We administered flexible asenapine doses ranging from 5–20 mg/day to 119 voluntarily hospitalized patients with Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR) BD-I diagnosis, with or without SUD. Patients were assessed with clinician-rated questionnaires [i.e. Brief Psychiatric Rating Scale (BPRS), Young Mania Rating Scale (YMRS), Hamilton Depression Rating Scale (HDRS), Hamilton Anxiety Rating Scale (HARS), and Global Assessment of Functioning (GAF)]. Assessments were carried out at baseline (T0, prior to treatment), and 3 (T1), 7 (T2), 15 (T3), and 30 days (T4) after starting treatment for all clinical scales and at T0 and T4 for the GAF. Results: Patients improved on all scales (p < 0.001) across all timepoints, as shown both by paired-sample comparisons and by applying a repeated-measures, generalized linear model (GLM). Patients without comorbid SUD showed greater reductions in BPRS scores at T2 and T3, greater reduction in YMRS scores at T3, and lower HARS scores at all timepoints. HDRS scores did not differ between the two groups at any timepoint. However, the reduction in HARS scores in the comorbid group was stronger than in the BD-I only group, albeit not significantly. Side effects were few and mild-to-moderate. Conclusions: The open-label design and the relatively short observation period may expose to both type I and type II statistical errors (false positive and false negatives). Asenapine showed effectiveness and safety in hospitalized BD-I patients. Its effect was stronger in patients without comorbid SUD.
Keywords: anxiety, asenapine, atypical antipsychotic drugs, bipolar disorder, substance use disorder
Introduction Bipolar disorder (BD) is a circular, chronic, progressive mood disorder characterized by major depressive episodes alternating with manic/hypomanic or mixed episodes [Judd et al. 2002; Leboyer and Kupfer, 2010]. BD with a history of a manic episode is type I (BD-I), whereas BD without manic episode history is type II [American Psychiatric Association, 1987, 2000]. Combined
estimated prevalence of type I and type II BD ranges from 0.5–2% [Warren and Dubovsky, 2013]. The prevalence of BD rises to 4.4–6.4% when adding subthreshold/subsyndromal forms [Merikangas et al. 2011]. BD is one of the main causes of disability worldwide, being associated to important psychological and social consequences, long-lasting
Correspondence to: Ilaria Cuomo, MD Villa von Siebenthal Neuropsychiatric Clinic, Genzano di Roma, Via della Madonnina 1, 00045 Genzano di Roma, Italy [email protected] Sergio De Filippis, MD Camilla Fini, MD Villa von Siebenthal, Genzano di Roma, Italy Department of Neurosciences, Mental Health, and Sensory Organs (NESMOS), School of Medicine and Psychology, Sapienza University, Rome, Italy Georgios D. Kotzalidis, MD, PhD Daniela Pucci, MD Matteo Caloro, MD Paolo Girardi, MD Department of Neurosciences, Mental Health, and Sensory Organs (NESMOS), School of Medicine and Psychology, Sapienza University, Rome, Italy Pietro Zingaretti, MSc Raffaella Porrari, MSc Paola Motta, MD Villa von Siebenthal, Genzano di Roma, Italy
http://tpp.sagepub.com 67
Therapeutic Advances in Psychopharmacology 7(2) unemployment, and medical comorbidity [Zimmerman et al. 2010; Merikangas et al. 2011]. BD has a high mortality rate that can be partly attributed to suicide (BD patients have the highest suicide risk after first hospital contact [Nordentoft et al. 2011] and their lifetime suicide attempt rate is 10–15%), to accidents, to a reckless dysmetabolizing lifestyle, and to the negative consequences of substance abuse [Craig et al. 2006; Khalsa et al. 2008; Young et al. 2013]. Due to its recurrent nature, patients present post-onset symptoms for almost half of their lives; this clinical and epidemiological finding imposes effective [Judd et al. 2002; Collins et al. 2011] and safe treatment that may ensure compliance, since the lack of treatment adherence is the most common cause of relapse or recurrence [Gutiérrez-Rojas et al. 2010]. Many second generation antipsychotics (SGAs) have been approved for acute, subacute, and maintenance treatment of BD. According to the World Federation of Societies of Biological Psychiatry (WFSBP) [Grunze et al. 2010] and to the Canadian Network for Mood and Anxiety Treatments (CANMAT) guidelines [Grunze et al. 2013], SGAs are first choice treatment in managing manic episodes, either in monotherapy or in association with mood stabilizers; quetiapine and olanzapine have obtained fair results also in the control of depressive episodes [Grunze et al. 2010, 2013; Yatham et al. 2013]. Asenapine has been recently approved in Europe for the treatment of moderate-to-severe manic episodes in adults, whereas in the US and some other countries it is used in the acute treatment of schizophrenia. Asenapine blocks 5-HT2A, 5-HT2B, 5-HT2C, 5-HT6 and 5-HT7 serotonin receptors, dopamine D2, D3 and D4 receptors, and α1A, α2A and α2C adrenoceptors [Szegedi et al. 2011; Azorin et al. 2013; Young et al. 2013]. Its moderate affinity for histamine receptors and almost complete lack of affinity for muscarinic acetylcholine receptors may explain its low propensity for metabolic changes [Potkin, 2011]. Clinical studies of asenapine to date showed efficacy in acute manic and mixed episodes [Panagides et al. 2007; McIntyre et al. 2010a], possibly in controlling depressive symptoms [Szegedi et al. 2011], and in maintenance [McIntyre et al. 2010b]. However, currently available data are insufficient for drawing conclusions, hence the need for further studies.
While there is consensus as to the importance of dopamine receptor blockade in mediating the antipsychotic effects of antipsychotics, and also regarding the importance of accumbens dopaminergic transmission in the maintenance of addictive behaviour [di Chiara et al. 2004], there is no clear indication for the use of atypical antipsychotics in the treatment of substance use disorders (SUDs). A study found clozapine to reduce symptoms of substance dependence more than olanzapine, and this has been attributed to the faster dissociation of the former from the D2 receptor [Machielsen and de Haan, 2009]. Although asenapine shows not so fast a dissociation from D2 receptors, it nevertheless blocks the D3 and D4 dopamine receptors, that have been linked to addiction [di Ciano et al. 2014; le Foll et al. 2014]. So it is possible that this drug improves sideways both the addiction and the psychosis. If true, we may expect a differential response of people with BD-I and SUD comorbidity. Our aim was to assess differences in the clinical response to asenapine between patients with BD-I patients alone and BD-I patients comorbid with SUD from a cohort of voluntarily hospitalized BD-I patients observed in a naturalistic setting. Material and methods Patients The study has been conducted in adult patients (aged 18–60) with BD- I who were voluntarily admitted between May 2014 and March 2015 at the Neuropsychiatric Hospital Villa von Siebenthal, Genzano, Rome, Italy. We recruited consecutive patients with DSM-IV-TR [American Psychiatric Association, 2000] BD-I on asenapine; each patient received the minimal effective dose. Diagnosis was confirmed through the Structured Clinical Interview for DSM-IV-TR Axis I Disorders (SCID-I) [First et al. 2002]. Patients who were on mood stabilizers or benzodiazepines were allowed to keep this regimen unaltered during the course of the study. Excluded were patients with neurological disorders, and intellectual disability. Assessment scales Patients were assessed through clinician-rated clinical scales and a functioning scale at baseline
68 http://tpp.sagepub.com
SD Filippis, I Cuomo et al. (T0, start of the treatment), 3 days later (T1), 1 week later (T2), 15 days later (T3), and 1 month later (T4, endpoint). To minimize errors, all evaluations for each patient were carried out by the same trained psychiatrist or psychologist (PM, CF, PZ, RP). Cohen’s κ for interrater reliability was 0.87 for all instruments used; p < 0.0001 (i.e. high). History and sociodemographic data were collected in a purposely constructed database, where annotation was made also for past drug treatment history and psychotropic drug use. The following clinical scales were completed at T0, T1, T2, T3, and T4: •• Hamilton Depression Rating Scale (HDRS) [Hamilton, 1960]: this is a scale sensitive to change that measures the severity of depressive symptoms. It contains an important proportion of somatic symptoms. It is a clinician-rated 21-item scale whose first 17 items are added to obtain the total score; single items are Likert, ranging 0–4 (8 items) or 0–2 (9 items); 0–7 is normal, 8–13 mild depression, 14–18 moderate depression, 19–22 severe depression and ⩾23 very severe depression. In antidepressant clinical trial research, a drop of at least 50% from baseline scores is considered as treatment response, while a score
